Crohn's disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD) characterized by chronic inflammatory responses within the intestinal tract. Genome-wide association studies (GWAS) examining the frequencies of single nucleotide polymorphisms (SNPs) in CD and UC patients have identified a large number of shared and unique susceptibility alleles. Using both GWAS and candidate gene approaches, polymorphisms in macrophage stimulating protein (MSP) have been identified that were thought to associate with susceptibility to both CD and UC. See e.g., Barrett et al., 2008, Nat Genet 40:955-62, and Consortium WTCC. 2007, Nature 447:661-78.
The likely causative allele responsible for this increased genetic risk is a non-synonymous coding SNP in MSP (rs3197999) that leads to an arginine to cysteine change at amino acid 689 (689R to 689C). See Goyette et al. 2008, Mucosal Immunol 1:131-8.
MSP is a plasminogen-related soluble growth factor expressed by the liver and secreted into the serum as an inactive single-chain protein (pro-MSP) incapable of binding its receptor, the Met-family receptor tyrosine kinase, Recepteur d'Origine Nantais (RON). Proteolytic cleavage of pro-MSP between R483 and V484 converts it into an active, two-chain disulfide-linked α/β heterodimer able to bind RON with high affinity and induce receptor signaling. See Gaudino et al., 1994, EMBO J 13:3524-32, and Wang et al., 1994, Science 266:117-9. The α-chain comprises an N-terminal PAN domain followed by four Kringle domains and the β-chain contains a C-terminal trypsin-like serine protease domain. pro-MSP can be proteolytically activated by a number of different serine proteases, including those involved in the coagulation cascade and induced during inflammatory responses. See e.g., Wang et al., 1994, J Biol Chem 269:3436-40. Thus, cleavage of MSP at sites of tissue damage leads to local activation of RON.
RON expression has been reported in epithelial cells, subsets of macrophages, neuroendocrine tissues, and developing bone, and has been linked to induction of epithelial cell proliferation, survival, migration and adherence to extracellular matrix. See e.g., Iwama et al., 1995, Blood 86:3394-403, Gaudino et al., 1995, Oncogene 11:2627-37, Danilkovitch et al., 1999, Exp Cell Res 248:575-82, and Danilkovitch et al., 2000, Mol Cell Biol 20:2218-27. More recently, the MSP-RON pathway has been proposed as a key negative regulator of inflammatory responses. Based primarily on studies of murine peritoneal macrophages stimulated with lipopolysaccharide and interferon-γ, RON signaling was found to suppress expression of pro-inflammatory factors and upregulate pathways that may be involved in tissue repair. See e.g., Chen et al., 1998, J Immunol, 161:4950-9, and Wilson et al., 2008, J Immunol, 181:2303-10. The suppressive role of RON in innate inflammatory responses has been supported by in vivo studies demonstrating that mice with targeted mutations in RON exhibit enhanced sensitivity to endotoxin challenge. See Waltz et al., 2001, J Clin Invest, 108:567-76. These in vitro and in vivo studies have led to the speculation that the increased genetic risk for IBD associated with the MSP 689C polymorphism is a direct consequence of altered binding between MSP and RON, and defects in RON-mediated inhibition of macrophage activation. See Khor et al., 2011, Nature 474:307-17, Gorlatova et al., 2011, PLoS One 6:e27269. Paradoxically, a more recent study found that the 689C polymorphism increases MSP stimulatory activity in a human monocytic cell line, inducing greater in vitro migration and proliferation. Hauser et al., 2012, Genes Immun 13:321-7.
Thus, a better understanding of the role of the MSP polymorphism in RON signaling and RON associated diseases, including IBD, and a better therapeutic for treatment is needed.